Hypertension is a major cause of chronic kidney disease in the Veterans that leads to end stage renal disease. The current therapeutic options in the clinical settings for this devastating condition are limited and often ineffective except dialysis or kidney transplantation. Therefore, a better understanding of the cellular and molecular mechanisms underlying the pathogenesis of hypertensive kidney disease is essential for developing effective strategies for the treatment of this progressive kidney disorder. We have studied the factors initiating and controlling the development of hypertensive kidney disease in a model of angiotensin II-induced hypertension and have discovered a critical and obligate role for immune-inflammatory dysregulation in the initiation of hypertensive kidney disease. We have found that the development of hypertensive kidney disease arises from the infiltration of mononuclear cells (monocytes/macrophage, T cells, and bone marrow-derived fibroblasts) into the kidney. The presence and activation of these cells from a CD45+ mononuclear population appear to be driven by and dependent upon induction of the chemokine, CXCL16, in renal tubular epithelial cells and is prevented by genetic disruption of CXCL16. Our preliminary studies have shown that induction of CXCL16 is associated with striking activation of PI3 kinase signaling in vivo, which is regulated by p PTEN) and the adaptor protein containing a PH domain, PTB domain, and leucine zipper motif 1 (APPL1) in vitro. Therefore, we hosphatase and tensin homologue deleted on chromosome ten (hypothesize that pathologic renal injury and fibrosis arises from immune-inflammatory dysregulation associated with induction of CXCL16 and subsequent activation of PI3 kinase /Akt. We propose that CXCL16 triggers PI3 kinase /Akt activation, initiating the uptake of circulating mononuclear cell population obligate to the resultant kidney injury and fibrosis, which is regulated by PTEN and APPL1. To test our hypothesis, we will pursue the following Specific Aims: Specific Aim 1 is to determine the role of PI3K in the recruitment of bone marrow-derived mononuclear cells in vitro and in vivo. Specific Aim 2 is to examine whether PTEN regulates PI3K/Akt signaling and inflammatory cell migration in vitro and in vivo. Specific Aim 3 is to evaluate whether APPL1 function as a negative regulator of PI3K/Akt signaling and inflammatory cell migration in vitro and in vivo. In summary, we plan to utilize biological, pharmacological, and genetic approaches to study the signaling mechanisms underlying immune-inflammatory dysregulation in the pathogenesis of Ang II- induced renal injury and fibrosis. Results from our studies will provide a new understanding of the molecular and cellular bases of hypertensive kidney disease and could lead to the development of novel therapeutic strategies for the treatment of hypertensive kidney disease.